TY - JOUR
T1 - Association of mitochondrial genomic background with risk of Multiple System Atrophy
AU - Valentino, Rebecca R.
AU - Heckman, Michael G.
AU - Johnson, Patrick W.
AU - Soto-Beasley, Alexandra I.
AU - Walton, Ronald L.
AU - Koga, Shunsuke
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Dickson, Dennis W.
AU - Ross, Owen A.
N1 - Funding Information:
We would like to thank all those who contributed towards our research, particularly the patients and families who donated brain and DNA samples - without their donation this study would not have been possible. Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and the Mayo Clinic Lewy Body Dementia Association (LBDA) Research Center of Excellence. Mayo Clinic is a LBD Center without Walls (U54-NS110435). Samples included in this study were clinical controls or donations to the Mayo Clinic Brain Bank in Jacksonville which is supported by CurePSP and Mayo Clinic funding. RRV designed the genotype assays and performed all laboratory analysis whilst MGH conducted, and is responsible for, all statistical data analysis. OAR had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Information:
OAR receives support from NIH ( R01-NS078086 , P50-NS072187 , U54-NS110435 , and U54-NS100693 ), DOD ( W81XWH-17-1-0249 ), The Little Family Foundation , the Michael J. Fox Foundation , the American Parkinson Disease Association (APDA), the Mayo Clinic Foundation , and the Center for Individualized Medicine . DWD receives support from NIH ( P50-AG016574 , U54-NS100693 , P50-NS072187 , P01-AG003949 ), CurePSP: Foundation for PSP | CBD and Related Disorders , the Tau Consortium , and the Robert E. Jacoby Professorship. OAR and DWD are both supported by NINDS Tau Center without Walls Program ( U54-NS100693 ) and NIH ( UG3-NS104095 ). ZKW is partially supported by the Mayo Clinic Center for Regenerative Medicine , the gifts from The Sol Goldman Charitable Trust , and the Donald G. and Jodi P. Heeringa Family , the Haworth Family Professorship in Neurodegenerative Diseases fund , and The Albertson Parkinson's Research Foundation . The funding organizations and sponsors had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Publisher Copyright:
© 2020
PY - 2020/12
Y1 - 2020/12
N2 - Introduction: Multiple system atrophy (MSA) is a rare, sporadic, and progressive neurodegenerative disease which is characterized neuropathologically by alpha-synuclein aggregates in oligodendroglia, and clinically by parkinsonism, ataxia, and autonomic dysfunction. Mitochondrial health influences neurodegeneration and defects in mitochondria, particularly in oxidative phosphorylation, are reported in MSA. Mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS proteins, however no study has investigated if mtDNA variation, in the form of mitochondrial haplogroups, influences MSA risk. Therefore, in this study we investigated the association of mtDNA haplogroups with MSA risk in a case-control manner. Methods: 176 pathologically confirmed MSA cases and 910 neurologically healthy controls from Mayo Clinic Jacksonville were genotyped for 39 unique mtDNA variants using Agena Biosciences MassARRAY iPlex technology. Mitochondrial haplogroups were assigned to mitochondrial phylogeny, and logistic regression models that were adjusted for age and sex were used to assess associations between mitochondrial haplogroups and risk of MSA. Results: After adjusting for multiple testing (P<0.0019 considered significant), no mitochondrial haplogroups were significantly associated with MSA risk. However, several nominally significant (P<0.05) associations were observed; haplogroup I was associated with a decreased risk of MSA (OR=0.09, P=0.021), while an increased risk of MSA was observed for haplogroups H3 (OR=2.43, P=0.017) and T1 and T2 (OR=2.04, P=0.007). Conclusion: This study investigated whether population-specific mtDNA variation is associated with risk of MSA, and our nominally significant findings suggest mitochondrial haplogroup background may influence MSA risk. Validation of these findings and additional meta-analytic studies will be important.
AB - Introduction: Multiple system atrophy (MSA) is a rare, sporadic, and progressive neurodegenerative disease which is characterized neuropathologically by alpha-synuclein aggregates in oligodendroglia, and clinically by parkinsonism, ataxia, and autonomic dysfunction. Mitochondrial health influences neurodegeneration and defects in mitochondria, particularly in oxidative phosphorylation, are reported in MSA. Mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS proteins, however no study has investigated if mtDNA variation, in the form of mitochondrial haplogroups, influences MSA risk. Therefore, in this study we investigated the association of mtDNA haplogroups with MSA risk in a case-control manner. Methods: 176 pathologically confirmed MSA cases and 910 neurologically healthy controls from Mayo Clinic Jacksonville were genotyped for 39 unique mtDNA variants using Agena Biosciences MassARRAY iPlex technology. Mitochondrial haplogroups were assigned to mitochondrial phylogeny, and logistic regression models that were adjusted for age and sex were used to assess associations between mitochondrial haplogroups and risk of MSA. Results: After adjusting for multiple testing (P<0.0019 considered significant), no mitochondrial haplogroups were significantly associated with MSA risk. However, several nominally significant (P<0.05) associations were observed; haplogroup I was associated with a decreased risk of MSA (OR=0.09, P=0.021), while an increased risk of MSA was observed for haplogroups H3 (OR=2.43, P=0.017) and T1 and T2 (OR=2.04, P=0.007). Conclusion: This study investigated whether population-specific mtDNA variation is associated with risk of MSA, and our nominally significant findings suggest mitochondrial haplogroup background may influence MSA risk. Validation of these findings and additional meta-analytic studies will be important.
KW - Alpha synuclein
KW - Genetics
KW - Mitochondrial haplogroup
KW - Multiple system atrophy
KW - Neurodegeneration
KW - mtDNA
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U2 - 10.1016/j.parkreldis.2020.10.040
DO - 10.1016/j.parkreldis.2020.10.040
M3 - Article
C2 - 33189969
AN - SCOPUS:85096165113
VL - 81
SP - 200
EP - 204
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
SN - 1353-8020
ER -